Extensive genetic analysis on taiwanese patients with inherited neuropathy

From 2001 to 2016, we have recruited more than 570 unrelated patients with inherited neuropathy, including 411 with Charcot-Marie-Tooth diseases (CMT), 76 with hereditary neuropathy with liability to pressure palsy (HNPP), 60 with transthyretin-mediated familial amyloidotic polyneuropathy and 16 with distal hereditary motor neuropathy (dHMN) in Taiwan. They are all of Han Chinese origin. To elucidate the genetic causes, we initially screened the CMT patients for PMP22 duplication and GJB1 mutations. Then, we screened both CMT and dHMN patients for mutations in 61 neuropathy-implicated genes by a targeted NGS panel. Furthermore, we utilized whole exome sequencing to analyze selected large pedigrees with molecularly unassigned inherited neuropathy. With these strategies, we identified the pathogenic mutations in 294 (71.5%) CMT patients, including 249 (86.5%) patients with demyelinating CMT and 45 (36.6%) patients with axonal CMT, as well as 3 (19%) dHMN patients. At the same time, we also identified that GNB4 and WARS are causal genes for CMT and dHMN, respectively, and the TFG p.Gly269Val mutation can cause a typical autosomal dominant axonal CMT with distal predominant symptoms, whereas TFG mutations were initially identified in Japanese patients with hereditary motor and sensory neuropathy with proximal dominance. In vitro functional studies also support the pathogenic role of mutations in GNB4, WARS, and TFG in neuropathy. Our studies demonstrate the mutational spectrum of inherited neuropathy in Taiwan, expand the list of causal genes of inherited neuropathy and disclose the importance of GNB4, WARS, and TFG in peripheral nerve functioning.